Adducts of 3-beta, 12-diacyloxy-5,7,9(11)-pregnatrien-20-ones



United States Patent ADDUCTS OF S-BE'IA,12-DIACYLOXY-5,7,9(11)-PREGNATRIEN-ZO-ONES Robert H. Levin and George B. Spero, KalamazooTownship, Kalamazoo County, and A Vern McIntosh, Jr., Kalamazoo, Mich.,assignors to The Upjohn Company, Kalamazoo, Mich., a corporation ofMichigan No Drawing. Application May 22, 1953, Serial No. 356,892

5 Claims. (Cl. 260239.55)

The present invention relates to adducts of 3-beta,12-diacyloxy-5,7,9(l1) pregnatrien ones with certain acids, anhydrides,imides, and esters of alpha, betaunsaturated dicarboxylic acids,particularly with maleic anhydride, maleimide, maleic acid and esters ofmaleic acids, and to processes for their production.

This application is a continuation-in-part of our copending applicationSerial No. 184,702, filed September 13, 1950, now U. S. Patent2,623,043, issued December 23, 1952, and of our copending applicationSerial No. 228,131, filed May 24, 1951, now abandoned, to whichreferences are made also for the preparation of the starting compoundsreferred to in this specification.

The adducts of 3-beta,12-diacyloxy-5,7,9(11)-pregnatrien-ZO-ones whichare the preferred embodiment of this invention are represented by thefollowing formula:

CH; CH:

in which Ac is an acyl radical of an organic carboxylic acid, especiallythose hydrocarbon aliphatic carboxylic acids containing from 1 to 8carbon atoms, inclusive, per molecule, and A is the adduct radical of analpha, beta-unsaturated carbonyl compound of the group consisting ofmaleic acid, maleic anhydride, maleimide, and dialkyl maleatescontaining from 1 to 8 carbon atoms, inclusive, in each alkyl radical.The acyl radicals (Ac) may be the same or different.

The principal object of the present invention is to provide novelcompounds which are useful in the preparation of steroid compoundscontaining an oxygen atom at carbon atom 11 in the steroid nucleus.Another object of the present invention is to provide a process for theproduction of these new compounds. Other objects and advantages of theinvention, some of which are referred to hereinafter, will be apparentto those skilled in the art to which the invention pertains.

The compounds of the present invention are useful in the preparation ofphysiologically active steroid compounds which possess an oxygen atom inposition 11 or 12. For example, heating a 3fi,l2-diacyloxy-5,7,9(11)-pregnatrien-ZO-ones with an amine as described by Levin et al. in U. S.Patent 2,577,776, issued December 11, .1951, removes the adduct groupyielding a 3,6,l2-diacyloxy-5,7,9(l1)-pregnatrien-20-one, which may behydrogenated to give 3B,12-diacyloxypregnane-20-one. Hydrolysis of3B,12-diacyloxypregnane-ZO-one with sodium hydroxide and oxidation withchromic acid results in the known pregnane-3,12,20-trione [Selye,Encyclopedia of Endocrinology, section I, volume IV, 1943, A. W. T.Franks Publishing Company, Montreal, p. 603; Hoehn and Mason, J. Am.Chem. Soc. 60, 1702 (1938); Reichstein et al., Helv. Chim. Acta 23, 747(1940)] which ICC has anesthetic and luteoid properties (Selyereference). When pregnane-3,12,20-trione is reacted with sodiumborohydride, the 3-keto and 12-keto groups are reduced. Treatment of thethus-obtained 3u,12-dihydroxypregnane- 20-one with acetic anhydrideyields the Set-acetate and oxidation of this compound with chromic acidproduces 3a-acetoxypregnane-12,20-dione which was converted by Gallagher(U. S. Patent 2,447,325, columns 1 and 2) into3u-hydroxypregnane-11,20-dione, which can be converted to cortisone bythe method of Kritchevsky, Garmaise and Gallagher, J. Am. Chem. Soc. 74,483 (1952).

Compounds of the present invention which are of particular interest arethose compounds conforming to the foregoing general formula and in whichAcO represents the radical resulting from the esterification of thehydroxyl group of the steroid with a carboxylic acid containing up toand including 8 carbon atoms. Such acids include formic, acetic,propionic, butyric, valeric, hexanoic, heptanoic, octanoic, succinic,glutaric, cyclopentanoic, cyclohexanoic, benzoic, toluic, and the like;the lower aliphatic acids of this group are preferred embodiments of theinvention. The acids may contain substituents such as halogen, alkyl andmethoxy radicals which are nonreactive with the reagents used in themethods described herein for the preparation of the compounds of theinvention. The adduct bridge (--A) that is represented between the 5 and8 positions of the steroid nucleus of these compounds may be representedby the graphic formulae:

and

the first of which represents that derived from maleic anhydride andmaleirnide (in which Y is an oxygen (--O) or an imino (-NH-) radical)while the second represents that derived from maleic acid and itsesters. In this second formula R represents hydrogen or an alkylradical. Such alkyl radicals (R) include the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, lauryl, heptyl, octyl, cyclopentyl,cyclohexyl, benzyl, and similar radicals, which may contain substituentssuch as halogen, methoxy and hydroxyl radicals, which are nonreactivewith the reagents used in the methods described herein for theirpreparation. While adducts of esters of maleic acids are describedherein with particular reference to those of dimethyl maleate, thepreferred embodiment of R in the foregoing second formula is alower-alkyl radical containing from 1 to 8 carbon atoms, inclusive.

The compounds of the present invention are usually colorless crystallinesolids. Those which are adducts formed from alpha, beta-unsaturatedacids and anhydrides are readily convertible to diester adducts byesterification with reagents such as diazoalkanes in accordance with themethod described by Wilds et al. in J. Org. Chem. 13, 763 (1948). Theadducts of dicarboxylic acids may be converted to adducts of thecorresponding dicarboxylic acid anhydrides by heat. The adducts of acidanhydrides may be converted to those of the corresponding acid byhydration with water.

The starting compounds from which the compounds of the present inventionare prepared are adducts of l2-hydroxy or 12 bromo 3pacy1oxy-5,7,9(11)-preg- Patented Dec. 21, 1954 natrien-ZO-ones withmaleic anhydride and its equivalents, having the general formula:

CH3 CH3 in which A and Ac have the significance hereinbefore specifiedand X is a bromine or hydroxyl radical. The preparation of thesecompounds, which is described in detail in our copending applicationSerial No. 184,702, filed September 13,1950, now U. S. Patent 2,623,043,issued December 23, 1952, consists essentially'of the following(alternative procedures are also described in our said copendingapplication):

(1) Dehydroergosterol is converted to an adduct with maleic anhydride orthe desired equivalent of maleic anhydride [I-I. Honigmann, Annalen 508,89-98 (1934)].

(2)-The adduct of dehydroergosterol is esterified by reaction, forexample, with benzoyl chloride, acetyl chloride or formic acid.

(3) The'resulting adduct of the 3B-acyloxydehydro- I ergosterol isozonized and then reduced in acid solution with zinc dust to obtain anadduct of a 3l8-acyloxybisnor- 5,7,9(l1)-cholatrien-22-al. (Seeapplication of Robert H. Levin, Serial No. 111,100, filed August 18,1949, now U. S. Patent 2,620,337 issued December 2, 1952, for details.)

(4) An enol ester of the resulting 3B-acyloxybisnor-5,7,9(1l)-cholatrien-22-a1 adduct 'is prepared and ozonized to theadduct of a 3,9-acylo'xy-5,7,9(11)-pregnatrien- 2 -one.

(5) The resulting adduct of the 3fi-acyloxy-5,7,9(11)-pregnatrien-ZO-one is 'reacted'with N-bromosuccinimide or bromine toproduce an adduct of a 3B-acyloxy-12- bromo-5,7,9( ll)-pregnatrien--one.

(6) The adduct of the -acyloxy-12-brorno-5,7,9(11)- prenatrien-ZO-one,on reaction with silver nitrate as described in Preparations 1 and 2hereinafter, yields the adduct of a3fl-acyloxy-12-hydroxy-5,7,9(11)-pregnatrien-20-one, if the 12-hydroxyinstead of the 12-bromo is desired as the starting compound. Othermethods for the preparation of the-12-hydr'oxy compound are described inour copending application Serial No. 228,132 filed May 24, 1951, nowabandoned.

In preparing the compounds of our invention from adducts of12-bromo-3B-acyloxy-5,7,9( 11 )-pregnatrien- 20-ones, either of twomethods may be used. In the first (illustrated'in Example 1hereinafter), the 12-bromo group is replaced by a 12-acyloxy group bythe use of a metal salt of theacid corresponding to theacyloxy group,for example, the acetoxy group may be introduced by the use of metalsalts of acetic acid such as sodium acetate, silver acetate, and thelike. Other salts, such as sodium benzoate'and the like, may be used tointroduce benzoxy and other acyloxy groups. Acetic acid and similaracids may be used as solvents in which to effect the reaction andnormally the reaction is etfected by heating at a temperature betweenapproximately 100 and approximately 180 degrees centigrade, the periodof heating to obtain optimum yields varying accordingly.

In the second method of converting an adduct of a12-bromo-3B-acyloxy-5,7,9(11)-pregnatrien-20-one to the desired adductof a 3B,12-diacyloxy-5,7,9(11)-pregnatrien-20-one (which is illustratedin Example 2 hereinafter), the 12-bromo compound is treated with zincmetal (dust) while in solution in the acid whose acyloxy group is to besubstituted for the bromine of the steroid adduct. The reaction isgenerally conducted by dissolving the adduct of the 12-bromo steroid inthe acid, for example, glacial acetic acid, and warmed; thereafter, tothe warm solution, zinc dust is added portionwise and the mixture heatedfor a short period after the addition has been completed. Thetemperatures which can be used are generally lower than those requiredwhen the acylation is effected with a salt of the acid, as in the firstmethod, and are preferably in the range between approximately 50 andapproximately degrees centigrade. Although zinc dust used in suchreactions has heretofore acted solely as a reducing agent, effectingreplacement of the bromo substituent by hydrogen, in this particularreaction the acyloxy radical replaces the bromine in the steroid adduct.

To convert an adduct of a 12-hydroxy-3p-acyloxy-5,7,9(11)-pregnatrien-20-one to the desired 313,12-diacyloxy derivative,esterification may be effected with an acid anhydride or acyl halide,such as acetic anhydride and acetyl chloride. Acids themselves may beused for the esterification but in such event it is preferable to add anesterification catalyst such as sulfuric acid, paratoluenesulfonic acidand the like, to facilitate the reaction. When using acid anhydrides andhalides and acids with esterification catalysts, the reaction mixturesare generally heated for several hours under gentle reflux but thetemperatures of heating may be varied between approximately 100 andapproximately 180 degrees centigrade. Pyridine may be used to facilitatethe esterification by acid anhydrides and halides, in which event lowerreaction temperatures, namely, room temperature and approximatelydegrees centigrade, can be used. Such a process is illustrated inExample 3 hereinafter.

The acids and salts and acid derivatives (anhydrides and halides) whichmay be used in accordance with the foregoing procedures are thoseconforming to the definition of the acyl group (Ac) hereinbeforespecified and include acetic, propionic, butyric, valeric hexanoic,octanoic, benzoic, ortho-toluic, chloro, acetic and methoxybenzoicacids, their metal salts, their anhydrides. and their chlorides andbromides.

These processes are particularly applicable to the preparation of maleicanhydride, maleimide and dialkyl. If maleic acid adducts are used as,

maleate adducts. starting materials, they are either partially orentirely converted to maleic anhydride adducts; furthermore, attempts tohydrolyze maleic anhydride adducts directly with acids or bases tomaleic acid adducts may result in partial or complete hydrolysis of theacyloxy radicals of the steroid nucleus.

Typical processesfor producing typical compounds of this invention aredescribed in the examples which follow. It is to be understood thatthere are merely illustrative and are not to be construed as limiting.

Example 1.]VIaleic anhydride adduct of 38,12-diacet0xy- 5 ,7,9(1 1)-pregnatrien-2Q-one One half (0.5) gram of the maleic anhydride adductof 3fl-acetoxy-12-bromo-5,7,9( 1 1) pregnatrien 20 one (melting point,216-218 degrees centigrade;. prepared-as gram of3B,12-diacetoxy-5,7,9(11)-pregnatrien-20-one.

maleic anhydride adduct, melting point 232-245 degrees centigrade,crystallized; the crystals were filteredfrorn the solution. water raisedthe melting point to 248-250 degrees centigrade. [a] +256 degrees(chloroform).

Analysis.-CalculatedforCsgHzrOs: C, 68.21; H, 6.71..

Found: C, 67.65; H, 6.55.

Example 2.Dimethyl maleaze adduct of 3,8,12-diacetqxy- 5,7,9(11-pregnatrien-20-0ne A solution of 2.7 grams of the dimethyl maleateadduct of 3 B-acetoxy-12-bromo-5 ,7,9 1 1) pregnatrien 20 one I (meltingpoint, 207.5-211 degrees centigrade; prepared as described in ourcopending application Serial No. 184,702, now US. Patent 2,623,043) in100 milliliters of glacial acetic acid was warmed on the steam bath,

Ten (10) grams of zinc dustwas then added portion-wise to the Warmsolution over a periodof 10 minutes and A the mixture was heated for anadditional hour. The

Several recrystallizations from acetone-.

The same compound was obtained by treating 318,12-diacetoxy-5,7,9(11)-pregnatrien-20-one maleic anhydride adduct(Example 1) with diazomethane.

PREPARATION 1.MALEIC ANHYDRIDE ADDUCT OF 3 8- ACETOXY- 12-HYDROXY5 ,7 ,91 1 )-PREGNATRIEN-20-ONE To a solution of 1.5 grams of the maleicanhydride adduct of 3fi-acetoxy-12-bromo-5,7,9 1 l)-pregnatrien- 20-one(melting point, 216-218 degrees centigrade; prepared as described in ourcopending application Serial No. 184,702) in 150 milliliters of acetonewas added 60 milliliters of 0.1 normal silver nitrate solution. Theaddition was made portionwise with shaking. After one hour at roomtemperature, the silver bromide which formed was removed by filtrationand the filtrate diluted with water until crystallization began. Theproduct, filtered after cooling, was 1.2 grams of 3B-acetoxy-12-hydroxy-5,7,9(1 1 )-pregnatrien-20-one maleic anhydride adduct, meltingpoint 225-234 degrees centigrade. A sample recrystallized for analysismelted at 234-237 degrees centigrade. [a] +126.6 degrees (chloroform).

Analysis-Calculated for C27H3207Z C, 69.21; H, 6.89. Found: C, 69.84; H,7.02.

PREPARATION 2.DIMETHYL MALEATE ADDUCT OF 3,9- ACETOXY12-HYDROXY-5,7,9( 11 -PREGNATRIEN-20-ONE Similarly, by the method of Preparation 1, thecorresponding 12-bromo dimethyl maleate adduct that was used in Example2 hereinbefore was converted to 3,3- acetoxy 12 hydroxy5,7,9(11)-pregnatrien-20-one dimethyl maleate adduct, melting point205-214 degrees centigrade. [a] -|-139.6 degrees (chloroform).

Analysis.Calculated for CzsI-IssOa: C, 67.68; H, 7.44. Found: C, 67.70;H, 7.48.

Example 3.Maleic anhydride adduct 0 35,12- diaceloxy-5,7,9 (11)-pregnatrien-20-one A solution of 1.86 grams of the maleic anhydrideadduct of 3 B-acetoxy- 12-hydroxy-5 ,7 ,9( 1 1 )-'pregnatrien- 20-one(Preparation 1) in 30 milliliters of pyridine and 30 milliliters ofacetic anhydride was heated on the steam bath for 45 minutes, cooled andpoured into ice water. The resulting precipitate, which weighed 2.0grams and had a melting point of 230-235 degrees centigrade, wascollected and recrystallized from dilute aqueous acetone. The meltingpoint of the recrystallized maleic anhydride adduct of3,3,12-diacetoxy-5,7,9( 1 l)-pregnatrien-20-one was thereby raised to248-250 degrees centigrade.

Other examples In a manner similar to that described in Example 3, thedimethyl maleate adduct of 3,8-acetoxy-l2-hydroxy-5,7,9( 11)-pregnatrien-20-one (Preparation 2) can be reacted in pyridine withacetic anhydride, propionic anhydride and the like, to yield thecorresponding 12-acyloxy derivatives. The dimethyl maleate adduct of3fl,l2-diacetoxy-5,7,9(l1)-pregnatrien-20-one has a melting point of216-218 degrees centigrade.

In a similar manner, maleic anhydride and other adducts of3B-acyloxy-12-hydroxy-5,7,9( 11 )-pregnatrien- 20-ones can be reactedwith benzoyl chloride CsHsCOCl in pyridine to give the correspondingadducts of 3B- acyloxy-12-benzoxy-5,7,9( 1 1 -pregnatrien-20-ones andother acylating agents may be used to produce the corresponding12-acylated steroid adducts.

The maleic acid and maleic anhydride adducts of 3,12-diacyloxy-5,7,9(ll)-pregnatrien-20-ones of this invention areconvertible to trienes, namely, 3,12-diacyloxy- 5,7,9(11)pregnatrien-20-ones, having double bonds at i the 5(6), 7(8) and 9(11)and the formula:

- CH3 CH:

wherein Ac has the significance hereinbefore specified. The removal ofthe maleic acid or maleic anhydride radical is effected by a pyrolysisreaction which consists essentially in heating the maleic acid or maleicanhydride adduct of the 3,12-diacy1oxy-5,7,9(11)-pregnatrien-ZO-one inthe presence of an organic amine at a temperature of approximately toapproximately 225 degrees centigrade, with or without the presence of anorganic solvent, and thereafter isolating the product triene. It is notnecessary to isolate the adducts from a reaction mixture in which theadduct was formed in order to effect the removal of the adduct radicalin accordance with such pyrolysis processes, since the entire reactionmixture or crude product may be treated. The desired triene can beobtained in a high degree of purity and in excellent yields.

Amines which can be used in this pyrolysis process include: secondaryaliphatic amines such as dimethylamine, diethylamine, dipropylamine,dibutylamine, diamylamine, dioctylamine; tertiary aliphatic amines suchas trimethylamine, triamylamine, methyldioctylamine, methyldiethylamine;secondary and tertiary cycloaliphatic amines such asN-methylcyclohexylamine, N,N- dirnethylcyclohexylamine,N,N-diethylcyclohexylamine; secondary and tertiary heterocyclic aminessuch as pyrrolidine, N-methylmorpholine, N-ethylpyrrolidine, morpholine,piperidine, N-methylpiperidine, 2-methylpiperidine,1,2-d1'methylpiperidine, 1,2,4-trimethylpiperidine,2,4,6-trimethylpiperidine, 1-ethyl-2,4,6-trirnethylpiperidine; aromaticheterocyclic amines such as pyridine, picoline, lutidine, collidine,quinoline, quinaldine, lepidine, 3-methylquinoline; secondary andtertiary carbocyclic aromatic amines such as N-methylaniline, N-ethylaniline, N'butylaniline, N-benzylaniline, N,Ndimethylaniline,N,N-diethylaniline, N,N-dibutylaniline, N,N-dibenzylaniline,N-methyltoluidine, N,N-diethy1- toluidine, N-ethylxylidine,N,N-dimethylxylidine; substituted aliphatic amines such asdiethylaminoethanol, dibutylaminoethanol, N-pyrrolidylethanol,N-piperidylethanol; substituted aromatic amines such asorthomethoxy-N,N-dimethylaniline, para-ethoxy-N,N-diethylaniline,para-chloro-N,N-dimethylaniline, para-bromo- N,N-diethylaniline,para-fluoro-N,N-dibutylaniline, N,N- dimethylmesidine (N,N dimethyl2,4,6 trimethylaniline); secondary and tertiary aralkyl amines such asmethylbenzylamine, dimethylbenzylamine, propylbenzylamine,diisopropylphenethylamine, diethylphenylisopropylamine; and primaryamines such as butylamine, hexylamine, octylamine, cyclohexylamine,aniline, toluidine, xylidine and the like.

The process comprises heating the selected 3-acyloxy- 12,20-dione maleicacid or maleic anhydride adduct to a temperature between approximately100 and approximately 225 degrees centigrade, preferably between and 200degrees centigrade, in the presence of an organic amine, removing excessamine, and recovering the product triene. The time required for thereaction is usually from approximately 1 to approximately 8 hours,depending upon such factors as the particular steroid adduct beingtreated, the amine employed, and temperature of reaction. Ordinarily, areaction period of approximately 4 hours is entirely satisfactory,although, at lower temperatures, a more extended period may be employedto advantage. The employment of pressure may in some cases beadvantageous, although it is in most cases preferred to conduct thepyrolysis reaction at atmospheric pressure. After completion of thereaction, the pure triene product can be recovered in conventionalmanner, such as by evaporation of solvent in vacuo, redissolving theresidue in an organic solvent,

e. g., methanol, diluting with water, extracting with ether, washing thesolution until neutral, drying, evaporating to dryness, chromatographingover an alumina column, and recrystallizing from an organic solvent, ifdesired.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is to be understood that alterations andmodifications may be made therein in conventional manner and that theinvention is limited solely by the scope of the claims appended hereto.

We claim:

1. An adduct of a 3fl,l2-diacyloxy-5,7,9(1l)-pregnatrien-ZO-one havingthe formula:

CH: CH:

in which Ac is an acyl radical of a hydrocarbon ali-" of maleic acid,maleic anhydride, and dialkyl maleates' whose alkyl radicals containfrom 1 to 8 carbon atoms, inclusive.

2. A maleic anhydride adduct of a 3;3,12-diacyloxy- 5 ,7,9( 1 l)-pregnatrien-20-one, wherein the acyloxy groups are of the formula AcO,Ac being the acyl radical of a hydrocarbon aliphatic carboxylic acidcontaining up to eight carbon atoms, inclusive.

3. A dialkyl maleate adduct of a 3fi,l2-diacyloxy-5,7,9(l1)-pregnatrien-20-one, wherein the acyloxy groups are of theformula AcO, Ac being the acyl radical of a hydrocarbon aliphaticcarboxylic acid containing up to eight carbon atoms, inclusive.

4. The maleic anhydride adduct of 3fi,12-diacetoxy' 5,7,9 1 1)-pregnatrien-20-one.

5. The dimethyl maleate adduct of 3,8,12-diacetoxy- 5,7,9( 1 1)-pr'egnatrien-20-ones.

No references cited.

1. AN ADDUCT OF A 3B,12-DIACYLOXY-5,7,9(11)-PREGNATRIEN-20-ONE HAVINGTHE FORMULA: